Fibrinogen Maracaibo: Hypo-Dysfibrinogenemia Caused by a Heterozygous Mutation in the Gen that Encodes for the Fibrinogen Aα Chain (G.1194G>A: P.Gly13>Glu) with Diminished Thrombin Generation

Abstract

Inherited fibrinogen disorders affect either the quantity (hypofibrinogenemia, fibrinogen levels <150 mg/dL) and afibrinogenemia, characterized by the complete deficiency of fibrinogen or the quality of the circulating fibrinogen (dysfibrinogenemia) or both (hypo-dysfibrinogenemia) [5]. Up to date, approximately 115 mutations have been reported that cause dysfibrinogenemia, 67 hypofibrinogenemia, 75 afibrinogenemia, and 13 hypodysfibrinogenemia; 101 in the Aα, 63 in the Bβ and 93 in the γ chain. About 50% of approximately more than 600 cases reported in the literature are silent [6,7]. Thrombin binds to its substrate, fibrinogen, and remains bound to the product, fibrin, after fibrinopeptides are removed [8,9]. Different studies have established that Asp7 to Val20, particularly residues on the N-terminal side P1 to P10 (nomenclature is that suggested by Abramovitz [10]) are required for the binding of fibrinogen´s fibrinopeptides to thrombin [11]. Within the sequence of fibrinopeptide A there are both critical (nonvariable) residues and those that can be modified without impairs thrombin catalytic activity [12]. The amino acid sequence of FpA between Asp7 and Arg16 is highly conserved among mammalian species, suggesting that this region is critical for thrombin binding [13,14]. Several abnormal fibrinogens